Abstract

Suppressed dopaminergic activity in a specific brain area may play a causal role in depression.

Major depressive disorder (MDD) is a heterogenous mental illness characterized by deficits in mood and reward processing. The ventral tegmental area (VTA) of the brain plays a critical role in regulating reward processing via its projection to the nucleus accumbens (NAc), and altered cellular function in VTA has been implicated in mediating depression. In a recent study, Zhong et al. begin to elucidate the cellular and molecular mechanisms underlying the dysregulation of VTA in depression. Using the widely validated chronic mild stress (CMS) mouse model, the authors verified that the depression-like behavior observed in this model is linked to decreased neuronal firing in the VTA.

The hyperpolarization-activated cation current (Ih), mediated by hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) channels, increases VTA firing. First, the authors tested whether Ih was suppressed in mice subjected to CMS by analyzing ex vivo brain slices. They discovered that in CMS-exposed mice, this current was suppressed in NAc-projecting VTA dopamine neurons, a pathway central to reward processing. The authors then demonstrated that pharmacological blockade of Ih suppressed VTA firing to a lesser extent in mice exposed to CMS than in nonstressed controls, providing additional evidence that decreased Ih contributed to the decreased VTA dopamine neuron firing observed in the CMS model.

Together, these findings demonstrate that CMS-induced depression-like behavior is at least partially mediated by decreased Ih in VTA dopaminergic neurons. Interestingly, earlier findings in mice exposed to chronic social defeat stress, another widely validated mouse model of depression, found that depression-like behavior was mediated by an increase in Ih. Thus, although both models suggest that dysregulation of VTA dopamine activity is central, further experiments will be necessary to determine the broader neural mechanisms whereby increases or decreases in VTA dopaminergic activity can converge to yield a common set of depression-related behavioral deficits.